In this work, a compartmental model to predict the concentration of hyperpolarized xenon (Xe) in the brain is developed based on the well established kinetics of Xe and estimated T1 values for the compartments. For the gaseous compartments, T1 was set to 12 seconds. For the tissue compartments, T1 was set to 6 seconds. Three gas delivery techniques were modeled: hyperventilation followed by breath-hold, continual breathing, and hyperventilation followed by continual breathing. Based on Xe CT, it is estimated that the maximum concentration of Xe that could be breathed is 80%. Based on this value and the estimated maximum polarization of 50%, the peak gray matter concentration of hyperpolarized Xe is calculated to be .036 mM. This leads to an estimated signal-to-noise ratio (SNR), at 2 T, for hyperpolarized Xe that is a factor of 50 lower than the SNR for proton MRI. The peak concentration of hyperpolarized Xe was also calculated over a wide range of gas and tissue T1 values. This model also predicts that the arterial blood will have a concentration of hyperpolarized Xe that is 10 times greater than the concentration in gray matter. An interactive version of the model can be found on the World Wide Web at http:(/)/ric.uthscsa.edu/staff /charlesmartinphd.html.

Administration, Inhalation↗

PubMedDate not supplied

RU 486 induced suppression of placental neutrophil elastase inhibitor levels.

After administration of RU 486 to pregnant cynomolgus monkeys, placental morphology varied from normal to pathological. In all cases (n = 5) circulating and placental PAPP-A levels were markedly suppressed by 76.0 per cent and 55.5 per cent, respectively. When fetal demise occurred within 24 h prior to caesarian section, morphological changes consistent with an active inflammatory (polymorphonuclear leukocytosis) reaction was readily observed at the utero-placental interface, degrading the chorionic villi. Whereas heparin-Sepharose fractionated aqueous extracts of placentae inhibited human neutrophil (or granulocyte) elastase (HGE) activity, extracts of placenta being degraded by host phagocytic-proteolytic defense system were rich in HGE activity. This study establishes: (1) the cynomolgus monkey as a model for PAPP-A studies, (2) that haemochorially implanted placentae produce PAPP-A, a heparin-binding inhibitor of HGE, (3) that administration of progesterone receptor antagonist suppressed placental PAPP-A synthesis, and (4) disrupted protease-protease inhibitor equilibrium at the feto-maternal interface. Thus supporting a role for progesterone in placental PAPP-A production and maintenance of a placental barrier against maternal phagocytic-proteolytic defenses.

Administration, Oral↗

PubMedDate not supplied

Preclinical experience with two selective progesterone receptor modulators on breast and endometrium.

Org 31710 and Org 33628 are two highly selective progesterone receptor modulators (PRMs) with respect to their anti-progestational and anti-glucocorticoid activity. The compounds have been studied both in vitro and in vivo. Org 33628 has approximately four times stronger anti-progestational activity in vitro than does Org 31710, and in rats it is about 15 times more potent in the pregnancy interruption test. Two main indications for the use of PRMs are breast cancer and fertility regulation. The effects of both Org 31710 and Org 33628 were tested in relevant models for these indications. The effects of the two compounds on breast tumor development were assessed and in rats using the DMBA model. Their potency in menses induction was tested in monkeys on a 4-day regimen in the luteal phase, and after a single dose at day 21 of the normal cycle, and under a continuous progestin treatment using desogestrel. The compounds were also tested alone in a continuous low-dose regimen. The effects on follicular development and ovulation were determined by measuring estradiol and progesterone levels. Cycle control was monitored by daily vaginal swabs. In the DMBA model, Org 31710 at oral doses of 0.8, 2.0, and 5.0 mg/kg showed a clear dose-related reduction in tumor load. With the two highest doses, an even lower tumor load was seen after a 3-week treatment period compared to the tumor load at the start of treatment. Org 33628 showed a similar efficacy as Org 31710 at a dose of 2.0 mg/kg. RU 486 after oral treatment was two times less potent in this model than Org 31710 and Org 33628. The efficacy of menses induction using the 4-day regimen is dependent on the time of administration relative to the progesterone peak in the luteal phase. The highest efficacy is achieved in the descending part of the peak, at which a 100% success rate is found with a dose of 1 mg/kg of either Org 31710 or Org 33628. In Cynomolgus monkeys, at a single dose of 15 mg/kg of Org 31710 or Org 33628 in the luteal phase, menses induction was achieved only in 60% of the treatment cycles. Surprisingly menses induction can be achieved with a single dose that is about a ten-times lower when the monkeys are treated continuously with desogestrel. Cycle control is better at low than at high doses of antiprogestin in combination with daily dosing of 4 microg/kg desogestrel. Despite the difference in receptor affinity, no difference between Org 31710 and Org 33628 was found in menses induction. In the continuous low-dose (1 mg/kg) regimen with the PRMs, follicular development occurs normally while ovulation is inhibited. Ovulation is resumed shortly after stopping treatment, and a normal menses occurs after the first progesterone peak. Both compounds may be interesting options for the prevention and treatment of breast cancer and for fertility control.

Animals↗

PubMedDate not supplied

In vivo effects of a potent GnRH antagonist ORG 30850: physiologic evidence that down-regulation of GnRH receptors does not occur.

OBJECTIVE: Our purpose was to determine the pituitary responsiveness to exogenous GnRH in GnRH antagonist-suppressed ovariectomized monkeys. METHODS: This was a prospective experimental non-human primate study performed at the research laboratories of The Jones Institute for Reproductive Medicine. Seventeen long-term ovariectomized cynomolgus monkeys were studied. INTERVENTIONS: The GnRH antagonist ORG 30850 was administered to long-term ovariectomized monkeys assigned to one of six groups: single subcutaneous injections in group A (n = 4), 0.3 mg/kg; group B (n = 4), 1.0 mg/kg; and group C (n = 3), 3.0 mg/kg; and six consecutive daily subcutaneous injections in group D (n = 2), 0.3 mg/kg; group E (n = 2), 1.0 mg/kg; and group F (n = 2), 3.0 mg/kg. Blood samples were collected daily from 10 days before treatment until 22 days after treatment, then weekly for 6 additional weeks. Intravenous GnRH stimulation tests (10 micrograms/kg) were performed on the day after vehicle injection (control) and the day after completion of treatment(s), and then at weekly intervals. The main outcome measures were serum levels of LH, FSH, and ORG 30850. RESULTS: Administration of ORG 30850 resulted in suppression (P < .05) of LH and FSH in all treatment groups. Long-term suppression (greater than 2 weeks) was evident in all primates receiving a cumulative dose of at least 1 mg/kg. Paradoxically, the responsiveness of the pituitary to exogenous GnRH was accentuated during the time of maximal tonic LH/FSH suppression. CONCLUSIONS: ORG 30850 is a potent long-acting GnRH antagonist. Furthermore, the present in vivo demonstration of heightened pituitary responsiveness to exogenous GnRH emphasizes the divergent mechanisms of action of GnRH antagonists and GnRH agonists.

Animals↗

PubMedDate not supplied

Proton relaxation enhancement associated with iodinated contrast agents in MR imaging of the CNS.

PURPOSE: To study the effects of iodinated radiographic contrast agents on proton relaxation in MR imaging. PATIENTS AND METHODS: Two patients were evaluated after the intrathecal administration of an iodinated nonionic contrast agent (Isovue) and five subjects with cranial tumors following the intravenous administration of an iodinated ionic contrast medium (Renografin). RESULTS: Both patients with subarachnoid iodinated contrast media demonstrated a relative reduction in T1 and/or T2 times using a spin-echo sequence, while four of five of the subjects with intracranial tumors (one glioma, one dural metastasis, three meningiomas) and intravenous enhancement revealed a visible MR effect. Confirmation of these in vivo observations was obtained by in vitro measurement of T1 and T2 while varying the concentration of the contrast media in saline. All iodinated contrast media showed progressively reduced relaxation times (T1 and T2) as the concentration of the agent was increased. The largest contributing relaxation mechanism is probably due to the binding and exchange of the surrounding water with the contrast molecules. CONCLUSION: The observed T1/T2 effects suggest that administration of iodinated contrast media in the period immediately prior to MR scanning may be contraindicated in selected cases due to the demonstrated alteration of MR signal intensity that may lead to diagnostic inaccuracies.

Brain Neoplasms↗